Acute Myeloid Leukemia
Conditions
Brief summary
The purpose of this study is to understand the safety profile of LY2181308 sodium administered in combination with idarubicin and cytarabine to patients with relapsed or refractory acute myeloid leukemia (AML).
Interventions
DRUGLY2181308 sodium
750 milligrams (mg) is administered as a 3-hour intravenous infusion on Days 1, 2, 3, 8, 15, 22 of Cycle 1 (28 days) and Days 1, 8, 15, 22 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.
DRUGcytarabine
1.5 grams per square meter (g/m²) will be administered as a 4-hour intravenous infusion on Days 3, 4, 5 of Cycle 1 (28 days) and Days 1, 2, 3 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.
DRUGidarubicin
12 milligrams per square meter (mg/m²) will be administered as a 30-minute intravenous infusion on Days 3, 4, 5 of Cycle 1 (28 days) and on Days 1, 2, 3 of Cycle 2 (28 days) until disease progression or unacceptable toxicity develops.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who have a diagnosis of acute myeloid leukemia that is relapsed or refractory to at least 1 prior treatment for leukemia, or patients with chronic myeloid leukemia (CML) who are in myeloid blast crisis which have failed at least 1 previous tyrosine kinase inhibitor (TK1). A baseline bone marrow assessment is required less than or equal to 96 hours prior to the first dose of study drug. * Must have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, cancer related hormone therapy, or other investigational therapy for at least 21 days for myelosuppressive agents (such as cytarabine, daunorubicin, and gemtuzumab ozogamicin) or 14 days for non-myelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (such as neurotoxicity, diarrhea, and mucositis) except for residual myelosuppression and alopecia. Hydroxyurea is permitted to control the peripheral blast cell count, but must be stopped at least 24 hours before study drug administration. * Must have adequate organ function. * Females must have a negative pregnancy test. Male and female patients must agree to use a reliable method of birth control during and for 6 months following the last dose of study drug. * Patients must be at least 18 years old.
Exclusion criteria
* Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a non-myelosuppressive or myelosuppressive agent, respectively. * Patients with acute promyelocytic leukemia (APML). * Major surgery within 4 weeks of study enrollment. * Patients with serious pre-existing medical conditions (at the discretion of the investigator). Because of the known cardiac toxicity of anthracyclines, patients with pre-existing ejection fraction (EF) less than or equal to 45% should not participate in this study. No patient should exceed the maximum exposure of anthracycline doses (for example, idarubicin greater than 120 mg/m²). * Patients with a second malignancy that could affect the interpretation of the results. * Patients with leukemic involvement of the central nervous system (CNS) by spinal fluid cytology or imaging. * Patients with known coagulopathy or bleeding disorder, other than leukemia related thrombocytopenia. Patients with severe of life threatening bleeding refractory to platelet transfusions are also excluded. * Concomitant anticoagulant therapy (with the exception of heparinized saline to maintain the patency of central venous catheters). * Women who are pregnant or breast feeding. * Patients with a known hypersensitivity to oligonucleotides, idarubicin, and/or cytarabine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (Safety Profile) | Start of treatment to study completion up to 6.7 months | Data are presented as number of participants who experienced serious adverse events (SAE) and possibly drug-related treatment-emergent adverse events (TEAE) during the study including the 21-day follow-up period. A summary of serious adverse events and other nonserious adverse events regardless of causality is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Response to LY2181308 Sodium in Combination With Idarubicin and Cytarabine (Remission Rates) | Baseline to progression of disease or death up to 6 months | Response is complete remission (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) + cytoreduction. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). Response rate is calculated as a total number of participants with CR or CRi or PR or cytoreduction divided by the total number of participants treated multiplied by 100. |
| Relapse-Free Survival | Baseline to progression of disease or death up to 6 months | Relapse-Free Survival was defined as the time from first objective status assessment of complete remission (CR) or CR with incomplete blood count recovery (CRi) or partial remission (PR) or cytoreduction to the first time of disease progression or death as a result of any cause. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). There were too few participants who had a documented progression of disease or death event amongst the participants with a response of CR, CRi, PR or cytoreduction to conduct the time-to-event analysis, thus the relapse-free survival was not analyzed. |
| Pharmacodynamics: Number of Participants With Survivin Protein Expression | 6 Months | Pharmacodynamics: Number of participants with Survivin Protein Expression. |
| Change From Baseline in Survivin Index at Day 2 | Baseline, Day 2 | Data presented are the ratio of Day 2 survivin index to the baseline survivin index. Survivin is a protein expressed in tumor cells, including acute myeloid leukemia (AML), which regulates mitosis and prevents tumor cell death. Survivin index was calculated as (\[blast survivin mean equivalent fluorochrome (MEFL) - blast isotypic control MEFL\]/blast isotypic control MEFL). |
| Area Under the Curve of LY2181308 Over the Dosing Interval | Day 3: 0,12,24,36,48,60,72,84,96,108,120,132 hours | Area under the curve of LY2181308 over the dosing interval |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up | Study treatment discontinuation up to 21 days post study treatment discontinuation | Deaths due to progressive disease (PD) and unknown cause are not considered adverse events. Deaths due to PD and unknown cause occurring during the 21-day follow-up period after treatment discontinuation are reported here and for those occurring while participants were on treatment are reported in the Participant Flow. Deaths due to serious adverse events occurred during the study including the 21-day follow-up period are reported in the Reported Adverse Events section. |
Countries
United States
Participant flow
Pre-assignment details
The reasons for discontinuation listed in the Participant Flow are the reasons the participant discontinued treatment. All participants who have completed at least 1 cycle of study drug were considered to have completed the study.
Participants by arm
| Arm | Count |
|---|---|
| LY2181308 750 milligrams (mg) was administered as a 3-hour intravenous infusion on Days 1, 2, 3, 8, 15, 22 of Cycle 1 and Days 1, 8, 15, 22 of Cycle 2 and beyond. Cycle length: 28 days. | 8 |
| LY2181308 + Idarubicin + Cytarabine LY2181308: 750 mg was administered as a 3-hour intravenous infusion on Days 1, 2, 3, 8, 15, 22 of Cycle 1 and Days 1, 8, 15, 22 of Cycle 2 and beyond.
Idarubicin: 12 milligrams per square meter (mg/m²) was administered as a 30-minute intravenous infusion on Days 3, 4, 5 of Cycle 1 and on Days 1, 2, 3 of Cycle 2 and beyond.
Cytarabine: 1.5 grams per square meter (g/m²) was administered as a 4-hour intravenous infusion on Days 3, 4, 5 of Cycle 1 and Days 1, 2, 3 of Cycle 2 and beyond.
Cycle length: 28 days. | 16 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Physician Decision | 0 | 7 |
| Overall Study | Progressive Disease | 5 | 5 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | LY2181308 + Idarubicin + Cytarabine | Total | LY2181308 |
|---|---|---|---|
| Age, Continuous | 48.22 years STANDARD_DEVIATION 14.72 | 52.23 years STANDARD_DEVIATION 15.88 | 60.26 years STANDARD_DEVIATION 15.93 |
| Race/Ethnicity, Customized African | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 11 Participants | 18 Participants | 7 Participants |
| Race/Ethnicity, Customized East Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized West Asian | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 16 Participants | 24 Participants | 8 Participants |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 16 / 16 |
| serious Total, serious adverse events | 6 / 8 | 13 / 16 |
Outcome results
Primary
Number of Participants With Adverse Events (Safety Profile)
Data are presented as number of participants who experienced serious adverse events (SAE) and possibly drug-related treatment-emergent adverse events (TEAE) during the study including the 21-day follow-up period. A summary of serious adverse events and other nonserious adverse events regardless of causality is located in the Reported Adverse Events section.
Time frame: Start of treatment to study completion up to 6.7 months
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LY2181308 | Number of Participants With Adverse Events (Safety Profile) | SAE | 6 Participants |
| LY2181308 | Number of Participants With Adverse Events (Safety Profile) | Drug-related TEAE | 2 Participants |
| LY2181308 + Idarubicin + Cytarabine | Number of Participants With Adverse Events (Safety Profile) | SAE | 13 Participants |
| LY2181308 + Idarubicin + Cytarabine | Number of Participants With Adverse Events (Safety Profile) | Drug-related TEAE | 11 Participants |
Secondary
Area Under the Curve of LY2181308 Over the Dosing Interval
Area under the curve of LY2181308 over the dosing interval
Time frame: Day 3: 0,12,24,36,48,60,72,84,96,108,120,132 hours
Population: All participants who received study drug and had pharmacokinetic (PK) data to calculate AUC.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2181308 | Area Under the Curve of LY2181308 Over the Dosing Interval | 216947 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 60 |
| LY2181308 + Idarubicin + Cytarabine | Area Under the Curve of LY2181308 Over the Dosing Interval | 185734 nanograms*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 45.7 |
Secondary
Change From Baseline in Survivin Index at Day 2
Data presented are the ratio of Day 2 survivin index to the baseline survivin index. Survivin is a protein expressed in tumor cells, including acute myeloid leukemia (AML), which regulates mitosis and prevents tumor cell death. Survivin index was calculated as (\[blast survivin mean equivalent fluorochrome (MEFL) - blast isotypic control MEFL\]/blast isotypic control MEFL).
Time frame: Baseline, Day 2
Population: All participants who received at least one dose of study drug and had both baseline and Day 2 survivin index measurements. Per protocol amendment, only participants in LY2181308 arm were analyzed for Survivin Index.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LY2181308 | Change From Baseline in Survivin Index at Day 2 | 0.43 ratio |
Secondary
Percentage of Participants With Response to LY2181308 Sodium in Combination With Idarubicin and Cytarabine (Remission Rates)
Response is complete remission (CR) + CR with incomplete blood count recovery (CRi) + partial remission (PR) + cytoreduction. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). Response rate is calculated as a total number of participants with CR or CRi or PR or cytoreduction divided by the total number of participants treated multiplied by 100.
Time frame: Baseline to progression of disease or death up to 6 months
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2181308 | Percentage of Participants With Response to LY2181308 Sodium in Combination With Idarubicin and Cytarabine (Remission Rates) | 0 percentage of participants |
| LY2181308 + Idarubicin + Cytarabine | Percentage of Participants With Response to LY2181308 Sodium in Combination With Idarubicin and Cytarabine (Remission Rates) | 56.3 percentage of participants |
Secondary
Pharmacodynamics: Number of Participants With Survivin Protein Expression
Pharmacodynamics: Number of participants with Survivin Protein Expression.
Time frame: 6 Months
Population: All participants who received at least one dose of study drug. Per protocol amendment, Survivin Protein Expression change was assessed for LY2181308 arm only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LY2181308 | Pharmacodynamics: Number of Participants With Survivin Protein Expression | 2 Participants |
Secondary
Relapse-Free Survival
Relapse-Free Survival was defined as the time from first objective status assessment of complete remission (CR) or CR with incomplete blood count recovery (CRi) or partial remission (PR) or cytoreduction to the first time of disease progression or death as a result of any cause. CR: fewer than 5% blasts based on a cell count of at least 200 cells from a bone marrow aspirate containing bone marrow spicules, in the setting of peripheral blood recovery to: platelets ≥100x10⁹/liter (L), neutrophils ≥10⁹/L. PR: defined as a decrease of at least 50% in blast count on the bone marrow aspirate; or cytoreduction (defined as a decrease in blast count not meeting the criteria for a PR or CR). There were too few participants who had a documented progression of disease or death event amongst the participants with a response of CR, CRi, PR or cytoreduction to conduct the time-to-event analysis, thus the relapse-free survival was not analyzed.
Time frame: Baseline to progression of disease or death up to 6 months
Population: Zero participants analyzed as no data collected on participants for relapse free survival due to no sufficient follow up on participants with response for time to event.
Other Pre-specified
Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up
Deaths due to progressive disease (PD) and unknown cause are not considered adverse events. Deaths due to PD and unknown cause occurring during the 21-day follow-up period after treatment discontinuation are reported here and for those occurring while participants were on treatment are reported in the Participant Flow. Deaths due to serious adverse events occurred during the study including the 21-day follow-up period are reported in the Reported Adverse Events section.
Time frame: Study treatment discontinuation up to 21 days post study treatment discontinuation
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LY2181308 | Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up | Death due to progressive disease | 1 Participants |
| LY2181308 | Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up | Death due to unknown cause | 1 Participants |
| LY2181308 + Idarubicin + Cytarabine | Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up | Death due to progressive disease | 0 Participants |
| LY2181308 + Idarubicin + Cytarabine | Number of Participants Who Died Due to Progressive Disease or Unknown Cause During the 21 Days Post Study Treatment Follow-Up | Death due to unknown cause | 0 Participants |